VCV000067656.37 - ClinVar

NM_000335.5(SCN5A):c.1336G>A (p.Glu446Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(17)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(3); Likely benign(7)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.1336G>A (p.Glu446Lys)

Variation ID: 67656 Accession: VCV000067656.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38605953 (GRCh38) [ NCBI UCSC ] 3: 38647444 (GRCh37) [ NCBI UCSC ] 3: 38622448 (NCBI36) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2014	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.1336G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Glu446Lys	missense
NM_001099404.2:c.1336G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Glu446Lys	missense
NM_001099405.2:c.1336G>A	NP_001092875.1:p.Glu446Lys	missense
NM_001160160.2:c.1336G>A	NP_001153632.1:p.Glu446Lys	missense
NM_001160161.2:c.1336G>A	NP_001153633.1:p.Glu446Lys	missense
NM_001354701.2:c.1336G>A	NP_001341630.1:p.Glu446Lys	missense
NM_198056.3:c.1336G>A	NP_932173.1:p.Glu446Lys	missense
NC_000003.12:g.38605953C>T
NC_000003.11:g.38647444C>T
NG_008934.1:g.48720G>A
LRG_289:g.48720G>A
LRG_289t1:c.1336G>A	LRG_289p1:p.Glu446Lys
LRG_289t2:c.1336G>A	LRG_289p2:p.Glu446Lys

... more HGVS ... less HGVS

Protein change

E446K

Other names

Canonical SPDI

NC_000003.12:38605952:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00063

Exome Aggregation Consortium (ExAC) 0.00072

The Genome Aggregation Database (gnomAD) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00010

1000 Genomes Project 30x 0.00047

1000 Genomes Project 0.00060

Links

dbSNP: rs199473339 ClinGen: CA014706 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN5A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3791	4234

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary dilated cardiomyopathy	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Apr 5, 2018	RCV000148863.15
not specified	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Dec 16, 2020	RCV000154845.16
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	May 9, 2022	RCV000617704.12
Brugada syndrome 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000987232.17
Progressive familial heart block, type 1A	Likely benign (1)	criteria provided, single submitter	Jan 31, 2019	RCV001144225.12
Dilated cardiomyopathy 1E	Likely benign (1)	criteria provided, single submitter	Jan 31, 2019	RCV001144226.12
Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	Jan 31, 2019	RCV001144227.12
Sick sinus syndrome 1	Benign (1)	criteria provided, single submitter	Jan 31, 2019	RCV001144228.12
Cardiac arrhythmia	Likely benign (1)	criteria provided, single submitter	Oct 20, 2018	RCV001842275.10
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV003539777.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Primary dilated cardiomyopathy Affected status: no Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Accession: SCV000050614.2 First in ClinVar: Jun 04, 2015 Last updated: May 05, 2018 Comments (2): The study set was not selected for affection status in relation to arrhythmia or cardiomyopathy. Pathogenicity categories were based on literature curation. See Pubmed ID:25741868 … (more) The study set was not selected for affection status in relation to arrhythmia or cardiomyopathy. Pathogenicity categories were based on literature curation. See Pubmed ID:25741868 for details. (less) Medical sequencing	Number of individuals with the variant: 1 Secondary finding: yes
Likely benign (Apr 09, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204527.5 First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019	Publications: PubMed (2) PubMed: 21596231‚ 22338672 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 2
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136481.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Primary dilated cardiomyopathy Affected status: yes Allele origin: unknown	Genetics and Genomics Program, Sidra Medicine Accession: SCV001434056.1 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Number of individuals with the variant: 1
Likely benign (Dec 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984695.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Likely benign (Oct 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000904470.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Jan 31, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1E Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304813.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 31, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304814.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Jan 31, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ventricular fibrillation, paroxysmal familial, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304815.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Jan 31, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sick sinus syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304816.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Likely benign (Jan 31, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Progressive familial heart block, type 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304812.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000760307.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809597.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Benign (May 09, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735952.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 21596231‚ 22338672‚ 23299917‚ 23861362‚ 25102755‚ 25351510‚ 25637381‚ 27896284 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005042413.6 First in ClinVar: May 12, 2024 Last updated: Oct 20, 2024	Comment: SCN5A: BS1, BS2 Number of individuals with the variant: 2
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Cardiomyopathy, dilated (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190607.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
not provided (-)	no classification provided Method: literature only	Primary dilated cardiomyopathy Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000089935.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (2) PubMed: 22581653‚ 21596231 Comment: This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:21596231). This is a literature report, and does not necessarily reflect … (more) This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:21596231). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
click to load more click to collapse

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant has been reported as associated with Dilated cardiomyopathy in the following publications (PMID:21596231). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy.	Nouhravesh N	Molecular genetics & genomic medicine	2016	PMID: 27896284
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
[Dilated cardiomyopathy caused by p.E446K mutation in SCN5A gene].	Zakliaz'minskaia EV	Kardiologiia	2014	PMID: 25102755
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
Torsades de pointes following acute myocardial infarction: evidence for a deadly link with a common genetic variant.	Crotti L	Heart rhythm	2012	PMID: 22338672
SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism.	McNair WP	Journal of the American College of Cardiology	2011	PMID: 21596231

Text-mined citations for rs199473339 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.1336G>A (p.Glu446Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473339 ...